Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants

ABSTRACT

The present invention provides improved oral dosage form formulations of efavirenz that are useful in the inhibition of human immunodeficiency virus (HIV), the prevention or treatment of infection by HIV, and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). In particular, the present invention relates to compressed tablets or capsules comprising efavirenz that contain one or more disintegrants that enhance the dissolution rate of the efavirenz in the gastrointestinal tract thereby improving the rate and extent of absorption of efavirenz in the body. The present invention also relates to the process of making such tablets or capsules.

FIELD OF THE INVENTION

[0001] The present invention provides improved oral dosage formformulations of efavirenz that are useful in the inhibition of humanimmunodeficiency virus (HIV), the prevention or treatment of infectionby HIV, and in the treatment of the resulting acquired immune deficiencysyndrome (AIDS). In particular, the present invention relates tocompressed tablets or capsules comprising efavirenz that contain one ormore disintegrants that enhance the dissolution rate of the efavirenz inthe gastrointestinal tract thereby improving the rate and extent ofabsorption of efavirenz in the body. The present invention also relatesto the process of making such tablets or capsules.

BACKGROUND OF THE INVENTION

[0002] In the dose titration of a patient, the objective is to attainand maintain a blood level of drug substance that exceeds the minimumeffective level required for response but does not exceed the minimumtoxic level. Absorption of a drug from an oral dosage form such as atablet or a capsule can be affected by properties of the formulation andits method of manufacture. This is particularly true when the drug haslow solubility in water, has a hydrophobic nature, and/or isadministered in high therapeutic doses. In such cases, dissolution ofthe drug from the dosage form in the gastrointestinal tract can be thelimiting factor that determines the rate and extent of absorption ofdrug into the body. Changes in the composition and/or method ofmanufacture of the dosage form can affect the dissolution rate.

[0003] An active area of research is in the discovery of new methods ofdrug formulation. Drug release from a solid dosage form can be enhancedby addition of materials referred to as disintegrants. Disintegrants aresubstances or a mixture of substances added to the drug formulation thatfacilitate the breakup or disintegration of the tablet or capsulecontents into smaller particles that dissolve more rapidly than in theabsence of the disintegrant (Handbook of Pharmaceutical Excipients,Ainley Wade and Paul J. Weller eds., 2d ed. 1994; The Theory andPractice of Industrial Pharmacy, Leon Lachman, Herbert A. Lieberman, andJoseph L. Kanig eds., 3rd ed. 1986; Disintegrating Agents in HardGelatin Capsules, John E. Botzolakis and Larry L. Augsburger, DrugDevelopment and Industrial Pharmacy 14(1), 29-41 1988). Materials thatserve as disintegrants include starches, clays, celluloses, algins, gumsand cross-linked polymers. A group of disintegrants referred to as“super-disintegrants” are generally used at a low level in the soliddosage form, typically 1 to 10% by weight relative to the total weightof the dosage unit. Examples of super-disintegrants are croscarmelose,crospovidone and sodium starch glycolate, which represent examples of across-linked cellulose, a cross-linked polymer and a cross-linkedstarch, respectively. EP 0,301,006 describes the use ofsuper-disintegrants to enhance the dissolution properties of tablet andcapsule formulations containing methylprednisolone, a glucocorticoidsteroid.

[0004] It is desirable to develop formulations where the tablet orcapsule disintegrates rapidly and the pharmaceutical agent dissolvesreadily. This is especially important where the pharmaceutical agent ishighly insoluble and/or must be administered in high-strength dosageforms.

[0005] This invention relates to new solid oral dosage form formulationscontaining the HIV drug efavirenz that enhance the dissolution rate ofefavirenz in the gastrointestinal tract in order to improve the rate andextent of absorption into the body, thereby improving its therapeuticeffect.

SUMMARY OF THE INVENTION

[0006] The present invention provides improved solid dosage formscontaining the non-nucleoside HIV reverse transcriptase inhibitor(NNRTI) drug efavirenz that disintegrate and dissolve rapidly therebyenhancing the therapeutic characteristics of the formulation. Thepresent invention also provides processes for the manufacture of capsuleand tablet formulations of efavirenz that allow a significantly higherstrength of efavirenz to be formulated in a single capsule or tablet.

[0007] An embodiment of the present invention includes formulations andprocesses for manufacturing tablets or capsules containing efavirenzusing a high-shear, wet granulation step where a very high level of asuper-disintegrant such as sodium starch glycolate is included in thewet granulation step.

[0008] Another embodiment of the present invention uses thesuper-disintegrant sodium starch glycolate in both a wet granulation anda dry blending step in the manufacturing process of tablets and capsulescontaining efavirenz. In a preferred embodiment of the manufacturingprocess the quantity of the sodium starch glycolate used in the wetgranulation step is in the range from about 20% to about 75% by weightrelative to the total dry weight of materials being granulated in thewet granulation step. More preferably the super-disintegrant componentin the wet granulation step is in the range from about 20% to about 55%by weight relative to the total dry weight of the materials beinggranulated in the wet granulation step.

[0009] In another embodiment of the present invention the range for theefavirenz in the wet granulation step can vary from about 25% to about80% by weight relative to the total dry weight of the materials beinggranulated in the wet granulation step. More preferably the drugsubstance component will range from about 45% to about 80% by weightrelative to total dry weight of the ingredients in the wet granulationstep.

[0010] In the present invention a surfactant such as sodium laurylsulfate is preferably used in the wet granulation step of the processfor the manufacture of the capsules or tablets of the present invention.The sodium lauryl sulfate is preferably dissolved in the wet granulatingfluid. Most preferably the sodium lauryl sulfate will range from about0.1% to about 5% by weight relative to the total dry weight of thematerials being granulated in the wet granulation step.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides improved oral dosage formformulations of efavirenz that are useful in the inhibition of humanimmunodeficiency virus (HIV), the prevention or treatment of infectionby HIV, and in the treatment of the resulting acquired immune deficiencysyndrome (AIDS). In particular, the present invention relates tocompressed tablets or capsules comprising efavirenz that contain one ormore disintegrants that enhance the dissolution rate of the efavirenz inthe gastrointestinal tract thereby improving the rate and extent ofabsorption of efavirenz in the body. The present invention also relatesto the process of making such tablets or capsules.

[0012] The active ingredient of the formulation of the present inventionis the NNRTI efavirenz, which is present in a therapeutically effectiveamount. Methods for the manufacture of efavirenz are disclosed in U.S.Pat. No. 5,519,021. The disclosure of U.S. Pat. No. 5,519,021 in itsentirety is hereby incorporated by reference. Efavirenz is(s)6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.

[0013] In addition to the active ingredient, solid dosage forms containa number of additional ingredients referred to as excipients. Theseexcipients include among others diluents, binders, lubricants, glidantsand disintegrants. Diluents are used to impart bulk to the formulationto make a tablet a practical size for compression. Examples of diluentsare lactose and cellulose. Binders are agents used to impart cohesivequalities to the powered material ensuring the tablet will remain intactafter compression, as well as improving the free-flowing qualities ofthe powder. Examples of typical binders are lactose, starch and varioussugars. Lubricants have several functions including preventing theadhesion of the tablets to the compression equipment and improving theflow of the granulation prior to compression or encapsulation.Lubricants are in most cases hydrophobic materials. Excessive use oflubricants can result in a formulation with reduced disintegrationand/or delayed dissolution of the drug substance. Glidants aresubstances that improve the flow characteristics of the granulationmaterial. Examples of glidants include talc and colloidal silicondioxide. Disintegrants are substances or a mixture of substances addedto a formulation to facilitate the breakup or disintegration of thesolid dosage form after administration. Materials that serve asdisintegrants include starches, clays, celluloses, algins, gums andcross-linked polymers. A group of disintegrants referred to as“super-disintegrants” generally are used at a low level in the soliddosage form, typically 1% to 10% by weight relative to the total weightof the dosage unit. Croscarmelose, crospovidone and sodium starchglycolate represent examples of a cross-linked cellulose, a cross-linkedpolymer and a cross-linked starch, respectively. Sodium starch glycolateswells seven- to twelve-fold in less than 30 seconds effectivelydisintegrating the granulations that contain it. Granulation refers to amixing technique by which the overall particle size of a formulation isincreased through the permanent aggregation of smaller particles. Wetgranulation refers to granulation that is accomplished by wetting thesmaller particles so they tack to one another. The newly-formed largerparticles remain intact after drying. In dry granulation, largerparticles are formed as a result of the compaction of the dryingredients, followed by milling of this compacted material intosuitably sized particles.

[0014] An embodiment of the present invention is a formulation and aprocess for manufacturing tablets or capsules using a high-shear, wetgranulation step in which a very high level of a super-disintegrant suchas sodium starch glycolate is included, followed by a dry blending stepthat incorporates additional quantities of super-disintegrant. In thepresent invention the amount of the super-disintegrant in the wetgranulation step of the manufacturing process is preferably in the rangeof about 20% to about 75% by weight relative to the total dry weight ofthe materials used in the wet granulation step. More preferably thesuper-disintegrant component will range from about 20% to about 55% byweight relative to the total dry weight of all of the ingredients in thewet granulation step of the manufacturing process. In general, the rangefor the HIV reverse transcriptase inhibitor in the wet granulation stepcan vary from about 25% to about 80% by weight relative to the total dryweight of all of the ingredients in the wet granulation step of themanufacturing process. More preferably the drug substance component willrange from about 45% to about 80% by weight relative to the total dryweight of all of the ingredients in the wet granulation step of themanufacturing process. Also included in the wet granulation step is asurfactant such as sodium lauryl sulfate, or another material thatimproves the wettability of the drug. Preferably the surfactantcomponent will range from about 0.1% to about 5% by weight relative tothe total weight of ingredients in the formulation. After the wetgranulation step, the material is dried, milled, and dry blended withother ingredients such as diluents, glidants, disintegrants, andlubricants. The result of the dry blending step is then filled intogelatin capsule shells or compressed into tablets. Gelatin capsules maycontain the active ingredient and powdered carriers such as lactose,starch, cellulose derivatives, magnesium stearate, stearic acid, and thelike. Similar diluents can be used to make compressed tablets. Bothcapsules and tablets can be manufactured as sustained release productsto provide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and to protect the tablet from the atmosphere, orenteric coated for selective disintegration in the gastrointestinaltract. Technology for the formation of solid dosage forms such ascapsules and compressed tablets, that utilize conventionalpharmaceutical manufacturing equipment for their purpose, is describedin detail in Remington's Pharmaceutical Sciences (Alfonso R. Gennaroed., ch. 89, 18th ed. 1990).

[0015] In one aspect of the present invention, it was discovered thatthe sodium starch glycolate acts as a highly swellable carrier materialonto which the efavirenz adheres during the wet granulation step of theprocess for the manufacture of tablets or capsules containing efavirenz.Granulation refers to a processing technique by which the overallparticle size of a formulation is increased through the permanentaggregation of smaller particles. Wet granulation refers to granulationthat is accomplished by wetting the smaller particles so they tack toone another. The newly-formed larger particles remain intact afterdrying. In the dry blending step of the process for the manufacture oftablets or capsules containing efavirenz, extragranular materials areadded to the granulation to impart other improved characteristics suchas flow and lubricity. The granulation is evenly blended throughout themixture.

[0016] The adherence of the drug efavirenz substance particles to thehydrated disintegrant sodium starch glycolate is accomplished byintimate mixing in the wet granulation step. In an embodiment of thepresent invention the quantity of sodium starch glycolate used in thewet granulation step is significantly higher than is typically used. Inthe present invention the wet granulation preferably contains about 20%to about 75% by weight sodium starch glycolate relative to the total dryweight of the ingredients of the wet granulation step, as opposed to the1-10% that is used in a typical wet granulation step (Handbook ofPharmaceutical Excipients, Ainley Wade and Paul J. Weller eds., 2d ed.1994; The Theory and Practice of Industrial Pharmacy, Leon Lachman,Herbert A. Lieberman, and Joseph L. Kanig eds., 3rd ed. 1986;Disintegrating Agents in Hard Gelatin Capsules, John E. Botzolakis andLarry L. Augsburger, Drug Development and Industrial Pharmacy 14(1),29-41 1988). During the wet granulation, efavirenz drug substanceparticles are attached to the surface of the sodium starch glycolateparticles. When these granules are exposed to the fluid in thegastrointestinal tract following the disintegration of the solid dosageform, the sodium starch glycolate rapidly swells and presents theattached efavirenz drug substance particles to the fluid allowing forrapid dissolution of the efavirenz.

[0017] The present invention provides capsule or compressed tabletpharmaceutical dosage forms comprising a therapeutically effectiveamount of efavirenz and comprising one or more disintegrants in anamount greater than about 10% by weight relative to the total weight ofthe contents of the capsule or the total weight of the tablet.

[0018] The disintegrant used in the present invention is preferablyselected from the group comprising modified starches, croscarmallosesodium, carboxymethylcellulose calcium and crospovidone.

[0019] The preferred disintegrant in the present invention is a modifiedstarch.

[0020] The more preferred disintegrant in the present invention is themodified starch sodium starch glycolate.

[0021] In the present invention the capsule formulation containsefavirenz present in an amount from about 5 to about 1000 mg percapsule.

[0022] It is preferred in the present invention that the capsuleformulation contain from about 5 to about 500 mg of efavirenz percapsule.

[0023] It is preferred in the present invention that the capsuleformulation contain from about 500 to about 1000 mg of efavirenz percapsule.

[0024] It is preferred in the present invention that the capsuleformulation contain from about 25 to about 350 mg of efavirenz percapsule.

[0025] It is preferred in the present invention that the capsuleformulation contain from about 50 to about 200 mg of efavirenz percapsule.

[0026] The compressed tablet of the present invention contains efavirenzin an amount from about 5 to about 800 mg per tablet.

[0027] The present invention provides for a pharmaceutical dosage formcomprising:

[0028] (a) a therapeutically effective amount of efavirenz;

[0029] (b) a surfactant;

[0030] (c) a disintegrant;

[0031] (d) a binder;

[0032] (e) a diluent;

[0033] (f) a lubricant;

[0034] (g) a glidant; and

[0035] (h) optionally additional pharmaceutically acceptable excipients;

[0036] wherein the disintegrant is selected from modified starches,croscarmallose sodium, carboxymethylcellulose calcium and crospovidoneand is present in an amount greater than about 10% by weight of thetotal dry weight of the capsule contents or the compressed tablet.

[0037] Another embodiment of the present invention provides a method formanufacturing a solid dosage form comprising the steps of:

[0038] (a) wet granulating the efavirenz and the intragranular sodiumstarch glycolate in a high-shear granulator using an aqueous solution ofsodium lauryl sulfate;

[0039] (b) drying result of step (a);

[0040] (c) milling result of step (b);

[0041] (d) dry blending result of step (c) with the extragranular sodiumstarch glycolate and additional pharmaceutically acceptable excipients;and

[0042] (e) encapsulating or compressing into tablets the result of step(d).

[0043] As used herein, the following terms and expressions have theindicated meanings.

[0044] “Sodium starch glycolate” refers to sodium carboxymethyl starch.

[0045] “Efavirenz” refers to the pharmacologically active ingredient(S)6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.The process for the synthesis of this compound is described in U.S. Pat.No. 5,519,021, which is hereby incorporated by reference.

[0046] “Therapeutically effective amount” is intended to mean an amountof a compound sufficient to produce the desired pharmacological effect.

[0047] “Modified starch” as used herein means any of severalwater-soluble polymers derived from a starch (corn, potato, tapioca) byacetylation, chlorination, acid hydrolysis, or enzymatic action.

EXAMPLES

[0048] In the following embodiments of the invention, the below-listedquantities of drug substance and additional components are combinedusing standard pharmaceutical manufacturing techniques. The resultingformulations are used to fill gelatin capsule shells or compressed intotablets utilizing standard pharmaceutical manufacturing techniques.

Example 1 Wet Granulation 100 mg Capsule Formulation

[0049] Method of manufacture: The efavirenz and intragranular sodiumstarch glycolate are mixed and then wet granulated after adding anaqueous solution of sodium lauryl sulfate. This wet mass may then bedried in a fluid bed, tray or other suitable dryer. The driedgranulation may then be milled to achieve a suitable particle sizedistribution and then is blended with the other ingredients. This blendis then filled into two piece hard gelatin capsule shells. IngredientAmount per capsule % efavirenz 100 mg 39.06 sodium lauryl sulfate 5 mg1.95 lactose, hydrous 57 mg 22.26 magnesium stearate 4 mg 1.56 sodiumstarch glycolate (intragranular) 80 mg 31.25 sodium starch glycolate(extragranular) 10 mg 3.91 Total Capsule Weight 256 mg

Example 2 Wet Granulation 100 mg Capsule Formulation

[0050] Method of manufacture: The efavirenz and intragranular sodiumstarch glycolate are granulated using an aqueous solution of sodiumlauryl sulfate. This wet mass may then be dried in a fluid bed, tray orother suitable dryer. The dried granulation may then be milled toachieve a suitable particle size distribution and then is blended withthe other ingredients. This blend is then filled into two piece hardgelatin capsule shells. Ingredient Amount per capsule % efavirenz 100 mg21.93 sodium lauryl sulfate 5 mg 1.10 sodium starch glycolate(intragranular) 50 mg 10.96 sodium starch glycolate (extragranular) 10mg 2.19 lactose, hydrous 277 mg 60.75 talc 8 mg 1.75 colloidal silicondioxide 4 mg 0.88 stearic acid 2 mg 0.44 Total Capsule Weight 456 mg

Example 3 Wet Granulation 300 mg Tablet Formulation

[0051] Method of manufacture: The efavirenz, sodium starch glycolate andmicrocrystalline cellulose are granulated using an aqueous solution ofsodium lauryl sulfate. This wet mass may then be dried in a fluid bed,tray or other suitable dryer. The dried granulation may then be milledto achieve the desired particle size distribution. This blend iscompressed into tablets. These tablets may be coated if desired.Ingredient Amount per tablet % efavirenz 300 mg 50.00 sodium laurylsulfate 12 mg 2.00 microcrystalline cellulose 120 mg 20.00 sodium starchglycolate 120 mg 20.00 lactose, hydrous 42 mg 7.00 magnesium stearate 6mg 1.00 Total Tablet Weight 600 mg

[0052] Assays were performed on capsule and tablet samples taken duringthe manufacturing processes described above. Analyses of the capsulesand tablets utilized USP specified procedures. The dissolution test usedUSP methodology Apparatus 2 (paddles at 50 RPM, 900 mL of 1% sodiumlauryl sulfate-distilled water solution at 37° C.) TABLE 1 DissolutionAssay of Capsule Formulation Capsule Formulation of Example 1: Time(minutes) % Dissolved 10 82.9 15 94.6 30 98.5 45 99.3 60 99.6

[0053] TABLE 2 Dissolution Assay of Tablet Formulation TabletFormulation of Example 3: Time (minutes) % Dissolved 10 78.0 15 91.5 30100.0 45 102.1 60 102.9

[0054] Assays were performed to determine dosage-form uniformity oncapsule and tablet samples taken during the manufacturing processesdescribed above. Capsules and tablets were tested for content uniformityfollowing USP specified guidelines. Results are shown in Table 3. “RSD”as used herein refers to relative standard deviation and is calculatedaccording to USP guidelines.

TABLE 3 Content Uniformity Assay

[0055] Capsules from Example 1:

[0056] content uniformity 100.2±1.7% (mean±RSD)

[0057] Tablets from Example 3:

[0058] content uniformity 104.3±0.7% (mean±RSD)

What is claimed is:
 1. A capsule or a compressed tablet pharmaceuticaldosage form comprising a therapeutically effective amount of efavirenzand greater than about 10% by weight of a disintegrant relative to thetotal dry weight of the pharmaceutical dosage form.
 2. A capsule orcompressed tablet according to claim 1 , wherein the disintegrant isselected from modified starches, croscarmallose sodium,carboxymethylcellulose calcium and crospovidone.
 3. A capsule orcompressed tablet according to claim 2 , wherein the disintegrant isselected from one or more modified starches.
 4. A capsule or compressedtablet according to claim 3 , wherein the modified starch is sodiumstarch glycolate.
 5. A capsule or compressed tablet according to anypreceding claim which is prepared using a wet granulation stepcontaining efavirenz and one or more modified starches, wherein themodified starch is present in the wet granulation step in an amount offrom about 10% to about 75% by weight relative to the total dry weightof the components of the wet granulation step.
 6. A capsule orcompressed tablet according to any preceding claim, wherein the modifiedstarch is present in the wet granulation step of the manufacturingprocess in an amount of from about 20% to about 55% by weight relativeto total dry weight of the components of the wet granulation step.
 7. Acapsule according to any preceding claim, wherein the efavirenz ispresent in the pharmaceutical dosage form in an amount of from about 5to about 1000 mg.
 8. A capsule according to any preceding claim, whereinthe efavirenz is present in the pharmaceutical dosage form in an amountof from about 5 to about 500 mg.
 9. A capsule according to any precedingclaim, wherein the efavirenz is present in the pharmaceutical dosageform in an amount of from 500 to about 1000 mg.
 10. A capsule accordingto any preceding claim, wherein the efavirenz is present in thepharmaceutical dosage form in an amount of from about 25 to about 350mg.
 11. A capsule according to any preceding claim, wherein theefavirenz is present in the pharmaceutical dosage form in an amount offrom about 50 to about 200 mg.
 12. A compressed tablet or capsuleaccording to claim 5 -11, wherein the wet granulation step is carriedout in the presence of sodium lauryl sulfate.
 13. A compressed tablet orcapsule according to claim 12 , wherein the sodium lauryl sulfate ispresent in an amount of about 0.1% to about 5% by weight relative tototal dry weight of the components of the wet granulation step.
 14. Acompressed tablet according to claim 1 , wherein the efavirenz ispresent in the pharmaceutical dosage form in an amount of from about 5to about 800 mg.
 15. A pharmaceutical dosage form comprising: (a) atherapeutically effective amount of efavirenz; (b) a surfactant; (c) adisintegrant; (d) a binder; (e) a diluent; (f) a lubricant; (g) aglidant; and (h) optionally additional pharmaceutically acceptableexcipients; wherein the disintegrant is selected from modified starches,croscarmallose sodium, carboxymethylcellulose calcium and crospovidoneand such disintegrant is present in an amount greater than about 10% byweight of the total dry weight of the capsule contents or the compressedtablet.
 16. A method for producing a capsule or a compressed tabletpharmaceutical dosage form comprising a therapeutically effective amountof efavirenz and greater than about 10% by weight of sodium starchglycolate relative to the total dry weight of the pharmaceutical dosageform comprising: (a) wet granulating efavirenz and sodium starchglycolate in the presence of an aqueous solution of sodium laurylsulfate; (b) drying the product of step (a); (c) milling the product ofstep (b); (d) dry blending the product of step (c) with sodium starchglycolate and additional pharmaceutically acceptable excipients; and (e)encapsulating or compressing into tablets the product of step (d).
 17. Amethod according to claim 16 , wherein: (i) the sodium starch glycolateof step (a) is present in an amount of from about 20% to about 75% byweight relative to the dry weight of all of the components of the wetgranulation step; and (ii) the sodium starch glycolate of step (d) ispresent in an amount of from about 1% to about 10% by weight relative tothe total dry weight of all of the components of the dry blending step.18. A method according to claim 16 , wherein: (i) the sodium starchglycolate of step (a) is present in an amount of from about 20% to about55% by weight relative to the total dry weight of all of the componentsof the wet granulation step; and (ii) the sodium starch glycolate ofstep (d) is present in an amount of from about 2% to about 4% by dryweight relative to the total weight of all of the components of the dryblending step.